Neuroprotective mechanisms of creatine occur in the absence of mitochondrial creatine kinase

Peter Klivenyi; Noel Y Calingasan; Anatoly Starkov; Irina G Stavrovskaya; Bruce S Kristal; Lichuan Yang; Bé Wieringa; M.Flint Beal

Neurobiology of Disease (Apr 2004)

Neuroprotective mechanisms of creatine occur in the absence of mitochondrial creatine kinase

Peter Klivenyi,
Noel Y Calingasan,
Anatoly Starkov,
Irina G Stavrovskaya,
Bruce S Kristal,
Lichuan Yang,
Bé Wieringa,
M.Flint Beal

Affiliations

Peter Klivenyi: Department of Neurology and Neuroscience, New York-Presbyterian Hospital, Weill Medical College of Cornell University, New York, NY 10021, USA; Dementia Research Service, Burke Medical Research Institute, White Plains, NY 10605, USA; Department of Biochemistry, Weill Medical College of Cornell University, New York, NY 10021, USA; Department of Cell Biology, University Medical Center St. Radboud, NCMLS, University of Nijmegen, Geert Grooteplein 28, 6525 GA, The Netherlands
Noel Y Calingasan: Department of Neurology and Neuroscience, New York-Presbyterian Hospital, Weill Medical College of Cornell University, New York, NY 10021, USA; Dementia Research Service, Burke Medical Research Institute, White Plains, NY 10605, USA; Department of Biochemistry, Weill Medical College of Cornell University, New York, NY 10021, USA; Department of Cell Biology, University Medical Center St. Radboud, NCMLS, University of Nijmegen, Geert Grooteplein 28, 6525 GA, The Netherlands
Anatoly Starkov: Department of Neurology and Neuroscience, New York-Presbyterian Hospital, Weill Medical College of Cornell University, New York, NY 10021, USA; Dementia Research Service, Burke Medical Research Institute, White Plains, NY 10605, USA; Department of Biochemistry, Weill Medical College of Cornell University, New York, NY 10021, USA; Department of Cell Biology, University Medical Center St. Radboud, NCMLS, University of Nijmegen, Geert Grooteplein 28, 6525 GA, The Netherlands
Irina G Stavrovskaya: Department of Neurology and Neuroscience, New York-Presbyterian Hospital, Weill Medical College of Cornell University, New York, NY 10021, USA; Dementia Research Service, Burke Medical Research Institute, White Plains, NY 10605, USA; Department of Biochemistry, Weill Medical College of Cornell University, New York, NY 10021, USA; Department of Cell Biology, University Medical Center St. Radboud, NCMLS, University of Nijmegen, Geert Grooteplein 28, 6525 GA, The Netherlands
Bruce S Kristal: Department of Neurology and Neuroscience, New York-Presbyterian Hospital, Weill Medical College of Cornell University, New York, NY 10021, USA; Dementia Research Service, Burke Medical Research Institute, White Plains, NY 10605, USA; Department of Biochemistry, Weill Medical College of Cornell University, New York, NY 10021, USA; Department of Cell Biology, University Medical Center St. Radboud, NCMLS, University of Nijmegen, Geert Grooteplein 28, 6525 GA, The Netherlands
Lichuan Yang: Department of Neurology and Neuroscience, New York-Presbyterian Hospital, Weill Medical College of Cornell University, New York, NY 10021, USA; Dementia Research Service, Burke Medical Research Institute, White Plains, NY 10605, USA; Department of Biochemistry, Weill Medical College of Cornell University, New York, NY 10021, USA; Department of Cell Biology, University Medical Center St. Radboud, NCMLS, University of Nijmegen, Geert Grooteplein 28, 6525 GA, The Netherlands
Bé Wieringa: Department of Neurology and Neuroscience, New York-Presbyterian Hospital, Weill Medical College of Cornell University, New York, NY 10021, USA; Dementia Research Service, Burke Medical Research Institute, White Plains, NY 10605, USA; Department of Biochemistry, Weill Medical College of Cornell University, New York, NY 10021, USA; Department of Cell Biology, University Medical Center St. Radboud, NCMLS, University of Nijmegen, Geert Grooteplein 28, 6525 GA, The Netherlands
M.Flint Beal: Department of Neurology and Neuroscience, New York-Presbyterian Hospital, Weill Medical College of Cornell University, New York, NY 10021, USA; Dementia Research Service, Burke Medical Research Institute, White Plains, NY 10605, USA; Department of Biochemistry, Weill Medical College of Cornell University, New York, NY 10021, USA; Department of Cell Biology, University Medical Center St. Radboud, NCMLS, University of Nijmegen, Geert Grooteplein 28, 6525 GA, The Netherlands

Journal volume & issue: Vol. 15, no. 3
pp. 610 – 617

Abstract

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There is substantial evidence that creatine administration exerts neuroprotective effects both in vitro and in vivo. The precise mechanisms for these neuroprotective effects however are as yet unclear. We investigated whether creatine administration could exert neuroprotective effects in mice deficient in ubiquitous mitochondrial creatine kinase (UbMi-CK). UbMi-CK-deficient mice showed increased sensitivity to 1-methyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-induced dopamine depletion and loss of tyrosine hydroxylase (TH) stained neurons. Isolated mitochondria from these mice showed no alterations in calcium retention, oxygen utilization, membrane potential, or swelling in response to a calcium challenge. Creatine administration significantly increased brain concentrations of both creatine and PCr in the UbMi-CK knockout mice. Creatine administration to the UbMi-CK-deficient mice exerted significant neuroprotective effects against MPTP toxicity that were comparable in magnitude to those seen in wild-type mice. These results suggest that the neuroprotective effects of creatine are not mediated by an effect on UbMi-CK to inhibit the mitochondrial permeability transition, and are more likely to be mediated by maintenance of appropriate ATP/ADP and PCr/Cr levels.

Published in Neurobiology of Disease

ISSN: 0969-9961 (Print); 1095-953X (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Medicine: Internal medicine: Neurosciences. Biological psychiatry. Neuropsychiatry
Website: https://www.journals.elsevier.com/neurobiology-of-disease

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